tbuckley/cabot-search huggingface dataset:
Characterization of patients with lung adenocarcinoma treated at a reference oncology center in northeastern Brazil and submitted to EGFR gene mutation research.
Authors: Isabelle Joyce de Lima Silva-Fernandes, Letícia Macedo Nicácio Andrade, Arthur Ernani Saldanha e Oliveira Lima, Maria Júlia Barbosa Bezerra, Maria Claudia dos Santos Luciano, Valeska Portela Lima, José de Brito Vieira Neto, Bruno Marques Soares, Aline Kimberly Almeida Rodrigues, Samara Regia Oliveira, Maria do Perpétuo Socorro Saldanha Cunha, Carlos Gustavo Hirth, Flávio da Silveira Bitencourt, Rosane Oliveira Sant'Ana, Paulo Goberlânio de Barros Silva
Journal: Journal of Clinical Oncology (2022)

e20548 Background: Lung cancer has the highest incidence and mortality worldwide. In Brazil, it is the second most common, and individualized therapy, although more efficient than traditional chemotherapy, is still a challenge for health services, especially in developing countries, as socioeconomic disparities make access to genetic testing difficult or treatment. Thus, it is understood that greater knowledge about the genetic profile and therapeutic response of different populations can contribute to policy changes that guarantee expanded access to individualized therapy. Methods: the EGFR gene mutation status was correlated with clinical-epidemiological, socioeconomic, treatment, and survival parameters of patients with lung adenocarcinoma treated from 2014 to 2021 at an oncology referral center in northeastern Brazil. Data were obtained retrospectively from the patient's charts at the Hospital Haroldo Juaçaba/Instituto do Câncer do Ceará. The X²/Fisher and Log-Rank Mantel-Cox tests were used to associate clinical variables and overall survival curves. The Research Ethics Committee approved the research under protocol number 3.544.754. Results: 586 patients tested, 157 (26.8%) had an EGFR mutation, with exon 19 deletion (n = 83, 52.9%). the most frequent followed by L858R (n = 54, 34.4%) and others (n = 30, 12.8%). The EGFR mutation was inversely associated with smoking history (p &lt; 0.001) and previous use of carboplatin plus paclitaxel (p &lt; 0.001). The median overall survival was 33 (95%CI = 25-41) months, and the presence of a mutation was not associated with a worse outcome (p = 0.146). Interestingly, patients with sensitivity mutation who used gefitinib (64.1%) did not show a significant difference in overall survival (p = 0.218). However, when stratifying analyzes according to mutation type, it was observed that patients with exon 19 deletion treated with gefitinib had greater median overall survival (32, 95%CI = 27-37 months) than patients with this mutation not treated with gefitinib (median = 15, 95%CI = 2-25 months) (p &lt; 0.001). Patients with the L858R type sensitivity mutation (p = 0.523) or other mutations (p = 0.439) did not experience significant benefits from gefitinib use. Conclusions: In the population studied, the exon 19 deletion was the most frequent and the only one associated with a substantial benefit from using gefitinib.
An open-label, multicenter, randomized phase II study of atezolizumab and bevacizumab with Y90 TARE in patients with unresectable hepatocellular carcinoma (HCC).
Authors: Aiwu Ruth He, Filip Banovac, Renuka V. Iyer, Michael Petroziello, Daniel Brown, Laura Williams Goff, Richard D. Kim, Nainesh Parikh, Beau Toskich, Kevin Kim, Yixing Jiang, Suvranu Ganguli, Matthew H. Kulke, Samantha Ann Armstrong, Matthew Johnson, Rachna T. Shroff, Gregory Woodhead
Journal: Journal of Clinical Oncology (2022)

TPS4177 Background: The anti–PD-L1 antibody atezolizumab (ATEZO) prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF bevacizumab (BEV) increases dendritic cell maturation, enhances T cell infiltration, and reduces myeloid-derived suppressor cells and regulatory T cells in tumors. ATEZO + BEV is FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. Locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire and increases tumor antigen release. We hypothesize that the Y90 TARE + BEV + ATEZO combination induces synergistic tumor killing and prolongs progression-free survival in patients (pts) receiving Y90 TARE (HR = 0.6 when compared to Y-90 TARE alone). Methods: Eligible pts have HCC that cannot be surgically resected (confirmed by pathology review), is at least BCLC stage B, and is outside Milan criteria. Other requirements include ECOG PS of 0-1 at screening, measurable disease by RECIST 1.1, no prior systemic therapy, and FLR estimated at ≥ 40% post local therapy. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE + ATEZO + BEV (Arm B). Pts will have TARE mapping followed by TARE treatment. In Arm B, pts will begin TARE treatment followed by BEV + ATEZO (4 wks [± 1 wk] later). Pts will have abdominal MRI or CT scans every 12 weeks and CT scans of the chest every 24 wks. The primary study objective is to assess and compare pts' progression-free survival (per mRECIST 1.1) in each study arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of pts in Arm B. Exploratory objectives are to define the use of cellular and circulating biomarkers in the prediction of improved clinical outcomes of pts in Arm B. Symptoms experienced by pts in both arms using patient-reported outcomes will be assessed. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of Y90 TARE + BEV + ATEZO in the first 10 pts randomized to Arm B for two cycles, and if there are no grade ≥ 3 unexpected toxicities possibly, probably, or definitely related to combined TARE + BEV + ATEZO, continue to accrue 128 pts in total (current enrollment n- = 5). Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.
Effect of adrenergic receptor antagonists on clinical outcomes in metastatic renal cell carcinoma.
Authors: Teja Ganta, Che-Kai Tsao
Journal: Journal of Clinical Oncology (2022)

e16520 Background: Adrenergic receptors (ADR) have a well-established role in kidney physiology, suggesting a possible role of ADR signaling in renal cell carcinoma (RCC). Preclinical studies have shown a possible anti-tumor effect of both alpha-adrenergic blockers (AB) and beta-adrenergic blockers (BB) on renal cancer cells. However, the literature is conflicting regarding the effect on clinical outcomes. In addition, there is no comprehensive analysis of what role these medications have specifically in RCC patients with metastatic disease. In this single health system retrospective study, we evaluate the effect of AB or BB prescription on cancer-specific outcomes in patients with metastatic RCC. Methods: Clinical data was abstracted from the electronic health record and the institutional cancer registry at The Mount Sinai Health System to include patients with RCC diagnosed with metastatic disease ( de novo or relapsed) between 2016-2020. Follow up data was recorded until a data lock of 4/1/2021. Multivariate Cox regression was used to evaluate the association of AB and BB prescription on overall survival (OS) for the entire cohort and progression free survival (PFS) for patients who received any first line therapy. Multivariate logistic regression was used to evaluate association of these medications with overall response rate (ORR) of first line therapies with available data on initial response. Analyses were controlled for clinical risk factors including age at diagnosis, sex, race, treatment plan including immunotherapy, and medical history of benign prostatic hyperplasia, hypertension, or heart failure. Data was analyzed using R version 4.1.0. Results: 133 patients were identified for inclusion in the study. 61% of cases are de novo metastatic and 39% are relapsed from previously resected disease. 71% are clear cell histology, 3.8 % are papillary, and the rest are unspecified/other. 84 patients (63%) received at least a 1 st line systemic therapy. AB or BB prescription alone is not associated with OS, PFS, or ORR. However, prescription of both AB and BB is associated with worse OS (HR 2.94 95% CI 1.13-7.68), worse PFS (HR 7.70 95% CI 1.80-33.0), and decreased odds of responding to 1 st line therapy (OR 0.06 95% CI 0.00-0.55) on multivariate analysis. Conclusions: The data suggests that the concurrent use of both an AB and BB in patients with metastatic RCC leads to worse clinical outcomes. What remains unclear is if there is a negative synergistic effect of these medications on RCC pathophysiology or if the prescription of these medications is associated with another negative confounding clinical factor. Since these medications are commonly utilized for cardiovascular disease, multivariate analyses attempted to control for these comorbidities. Future studies may add to this data by cataloging the severity of heart failure and doses of AB and BB medications used in a RCC cohort.
ETCTN 10437: A single-arm phase II study of bone-targeted sn-117m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.
Authors: Zin Myint, William H. St Clair, Peng Wang, Riham Khouli, Bryan P Lemieux, Dennis Cheek, Donglin Yan, Charles Kunos
Journal: Journal of Clinical Oncology (2022)

TPS5095 Background: Most patients with metastatic castration resistant prostate cancer (mCRPC) develop bone metastases with debilitating pain that is itself associated with shorter survival. Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain. To date, radium-223 dichloride is the first and only approved targeted alpha therapy for mCRPC; the major dose limitation is bone marrow toxicity with modest pain relief. Sn-117m-diethylenetriaminepentaacetic acid (DPTA), is a complex of a radioisotope of tin with DTPA. It emits a low-energy conversion electron and also yields a gamma emission. Sn-117m-DPTA localizes selectively in bone, and the limited range (0.2-0.3 mm) of its conversion electrons resulting in deeper tissue penetration with less radiation effects on bone marrow as compared to radium-223 dichloride. Srivastava et al. (1998) reported in a phase I/II study of patients with painful bone metastases from a variety of solid tumors, 45% of patients obtained reduction of pain by at least 50%, and 30% had complete relief of pain for more than two weeks after one injection. Thus, Sn-117m-DTPA has high palliative efficacy with little significant toxicity. Additional evaluation of this agent in mCRPC patients is urgently required. Methods: The study is a phase 2 single-arm clinical trial of Sn-117m-DPTA (20 mCi/70Kg or 0.28 mCi/kg) intravenously every 8 weeks for two injections for patients with mCRPC metastatic to at least two bone sites with at least one clinically meaningful pain site at baseline. Re-treatment with additional two cycles is allowed if patients meet re-treatment criteria. Key eligibility criteria include 1) refractory mCRPC patients who progressed on any lines of therapies 2) self-reported bone pain (≥4 on an 11-point pain intensity scale), and 3) must be on either regular pain medication or have undergone palliative radiation for bone pain within 12 weeks prior to starting study treatment. Key exclusion criteria include 1) visceral metastases and 2) malignant lymphadenopathy exceeding 3cm in short-axis diameter. Twenty-five patients will be enrolled with a primary objective to assess the efficacy of Sn-117m-DTPA on sustained pain response; defined as 1) achieving pain index ≤3 index within a 12-week period and 2) maintaining pain index ≤3 over a 16-week period. Secondary endpoints include patient reported outcomes, adverse events, progression-free survival and overall survival. Correlative aims include assessing blood (systemic inflammatory markers) and tissue biomarkers (gene sequencing and polo-like kinase-1) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 10 patients become evaluable. The study began enrolling patients in December 2021 and is ongoing. Clinical trial information: NCT04616547.
Phase 1a/b safety study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer (ADVANCED-1).
Authors: Jathin Bandari, Jacqueline Zummo, Khushboo Belani, Eppie Brown, McKenna Metcalf, Nuwan Nanayakkara
Journal: Journal of Clinical Oncology (2022)

TPS4620 Background: Bladder cancer is the most common malignancy involving the urinary system, resulting in approximately 18,000 deaths each year in the US. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guérin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for the treatment of high-grade (HG) NMIBC (consisting of HG Ta, T1, and carcinoma in situ [CIS]). TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. TARA-002 is manufactured using the same master cell bank as OK-432 (Picibanil) and is approved in Japan and Taiwan for the treatment of several oncology indications. Nonclinical toxicology studies with TARA-002 and nonclinical and clinical studies with OK-432 (a comparable product to TARA-002) support the starting dose for the planned Phase 1a/b study. Methods: ADVANCED-1 is a Phase 1a/b, dose finding, open-label study of intravesical instillation of TARA-002 in adults with HG NMIBC. The study includes a dose escalation phase (Phase 1a) and a dose expansion phase (Phase 1b). The objective of the study is to evaluate the safety and tolerability of TARA-002, to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) in the treatment of subjects with HG Ta or CIS ± Ta NMIBC during Phase 1a, and to further assess the safety and preliminary efficacy of TARA-002 in the treatment of subjects with CIS NMIBC with active disease during Phase 1b. For this first-in-human study, stage T1 is excluded. The study includes eligible male and female subjects ≥ 18 years of age who are unable to obtain BCG or have received at least one dose of intravesical BCG or chemotherapy. Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration for each subject includes 28 days of screening period, 6-week treatment period, and 6-week follow-up period. During the dose escalation phase (1a), up to 18 subjects with HG Ta or CIS ± Ta NMIBC are enrolled. Up to 3 dose levels are tested sequentially with 6 weekly intravesical doses, starting with the lowest dose using a 3+3 design in a dose escalation manner. At the established RP2D, the dose expansion phase (1b) will enroll approximately 12 new subjects with CIS ± Ta NMIBC with active disease and treat in the same manner to further assess the safety and preliminary efficacy of TARA-002. Phase 1a is currently open for enrollment. Clinical trial information: NCT05085977; NCT05085990.
Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma.
Authors: Radhika Bansal, Mizba Baksh, Jeremy Todd Larsen, Matthew Hathcock, David Dingli, Keith Stewart, Prashant Kapoor, Taxiarchis Kourelis, Suzanne R. Hayman, Rahma M. Warsame, Rafael Fonseca, Peter Leif Bergsagel, Sikander Ailawadhi, Shaji Kumar, Yi Lin
Journal: Journal of Clinical Oncology (2022)

8022 Background: Bone marrow (BM) assessment of minimal residual disease (MRD) is being considered as a surrogate endpoint in clinical trials and is prognostic for survival in multiple myeloma (MM). Timing of BM assessment is variable across Chimeric Antigen Receptor T cell (CART) therapy trials and differs from standard of care practice. BM myeloma cell clearance can be detected by month 1 post CART, even before serum immunofixation becomes negative. BM is still hypocellular at month 1, thus prognostic value of MRD negative (MRDneg) at this timepoint is unclear. We examined impact of Day 30 MRD status in patients (pts) who received CART at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CART between 8/2016 and 6/2021. PFS and OS were plotted by Kaplan-Meier method. Results: Sixty MM pts received CART and had BM biopsy at month 1. Median age was 62 yrs, 53% were male, and 78% were BM MRDneg by flow cytometry. Baseline demographics were similar between MRDneg and MRD+ (Table). Overall, 85% (40/47) who were month 1 BM MRDneg had i/u FLC&lt;normal. Patients who achieved CR/sCR had higher rates of BM MRDneg (100% vs 61%, p&lt;0.001) and i/u FLC&lt; normal (89% vs 58%, p&lt;0.001). At month 1, 24/60 (40%) pts had hypocellular BM. Serial BM samples at month 3 (n=35), 6 (n=28) and 12 (n=23) showed MRDneg rate of 93% (25/27), 56% (9/16) 58% (7/12), respectively.. Rate of hypocellularity was 54% (19/35), 32% (9/28) and 30% (7/23), respectively. Among the MRDneg/hypocellular pts at month 1, hypocellular BM was seen in 8/11 (73%) pts at month 3 and 2/4 (50%) pts at month 6 and 12. Compared to MRD+, pts who had BM MRDneg at months1 had longer PFS (Table). PFS was not statistically significantly different between pts who had BM MRDneg and were either hypocellular or not. MRDneg pts with i/u FLC&lt;normal at months1 had better median PFS compared to those who did not. (MRD+:2.9 months (1.2-NR). MRDneg/FLC&gt;normal: 4.9 months (2.3-NR). vs MRDneg/FLC&lt;normal:17.9 months (11.8-NR), p&lt;0.0001). Conclusions: Hypocellular BM is common in the 3 months post CART. Regardless of BM cellularity, BM MRDneg at month 1 correlates with deep response and prolonged PFS. Majority of BM MRDneg pts at month 1 also had FLC&lt;normal. BM MRDneg status and FLC normalization were associated with longer survival. Our data support the continued evaluation of BM early post CART infusion as a prognostic tool. [Table: see text]
A phase 1 trial of the bifunctional EGFR/TGFβ fusion protein BCA101 alone and in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Philippe L. Bedard, Alberto Hernando-Calvo, Richard D. Carvajal, Van K. Morris, Paul K. Paik, Dan Paul Zandberg, John M. Kaczmar, Liviu Niculescu, David Bohr, Ralf Reiners, Elham Gharakhani, Rachel Salazar, Sanela Bilic, Glenn J. Hanna
Journal: Journal of Clinical Oncology (2022)

2513 Background: BCA101 is a first-in-class bifunctional fusion protein consisting of an anti-EGFR monoclonal antibody (mAb) and TGFβ receptor 2 extracellular domain (TGFβRII-ECD). Herein, we report the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data of BCA101 as monotherapy and in combination with pembrolizumab among patients (pts) with advanced solid tumors refractory to standard therapies. Methods: Pts received BCA101 as a single agent (SA) or in combination with pembrolizumab at escalating doses in a parallel 3+3 design starting at 64 mg intravenously (IV) weekly (qw); and at 240 mg IV qw with pembrolizumab 200 mg IV q3w. Primary endpoint: safety and tolerability (CTCAE v5.0); dose limiting toxicity (DLT) period: 21 days. Secondary endpoints: overall response rate (ORR), PK/PD profile, progression-free survival (PFS), and changes in plasma and intra-tumoral TGFβ signaling assessed by SMAD2 phosphorylation. Results: As of 08-Feb-2022, 60 pts have received BCA101 (part A). Forty-five pts (colorectal, n=14; pancreatic, n=7; head and neck squamous cell carcinoma [HNSCC], n=6) received SA BCA101 at doses up to 1500 mg IV weekly. Fifteen subjects (SCC of the anal canal [SCAC], n=8; HNSCC, n=7) received BCA101 doses ranging from 240 to 1500 mg IV qw in combination with pembrolizumab. Maximum tolerated dose has not been reached. Common adverse events (AEs) attributed to BCA101 include rash (70%), fatigue (23%), pruritis and epistaxis (17% each); all grade (G)2 or less. One DLT was observed at the 1250 mg SA dose (G3 anemia, hematuria). No drug-related G4 AEs or deaths were observed. At data cutoff, best response in the SA arm was stable disease (SD) in 15/39 (39%) evaluable pts. In combination, partial response (PR) was observed in 3/11 (27%) evaluable pts (2 in SCAC, 1 in HNSCC) and a disease control rate (DCR) of 9/11 (82%). Two of 3 responders have been on study &gt;4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab. Saturation of the EGFR target was observed at BCA101 doses ≥750 mg. Dose proportional increase in Cmax and AUC were observed with doses of BCA101 750-1500 mg. Prolonged neutralization of plasma TGFβ1 was achieved at all doses ≥500 mg. Among paired tumor biopsies (n=23), pSMAD2 reduction up to 62% was observed at doses ≥500 mg. Conclusions: BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. A recommended dose of 1500 mg both as SA and in combination has advanced to the part B expansion phase for pts with HNSCC, SCAC, and cutaneous SCC. Clinical trial information: NCT04429542.